Double-sides sticking mechanism of vinblastine interacting with α, β-tubulin to get activity against cancer cells. Issue 15 (13th October 2019) - Zhou, Xiaowen
Abstract: Vinblastine (VLB) and its derivatives have been used for clinical first-line drugs to treat various cancers. Due to the resistance and serious side effects from using VLB and its derivatives, there is a need to discover and develop novel VLB derivatives with high activity against cancer cells. In order to better discover and develop new VLB derivatives, we need to study the structural basis of VLB's anti-cancer cytotoxicity and the mechanism of its interaction with α, β-tubulins. Based on the crystal structure of α, β-microtubule complex protein, the molecular dynamics method including the sampling PMF method was used to study the variation of dissociation free energy (Δ G ) of α, β-tubulins under different system conditions, and then from which to study the mechanism of the interaction between VLB and α, β-tubulins. The obtained results show that the dissociation of pure α, β-tubulins requires 197.8 kJ·mol −1 for Δ G . When the VLB molecule exists between the interface of α, β-tubulins, the dissociation Δ G of α, β-tubulins reaches 220.5 kJ·mol −1, which is greater than that of pure α, β-tubulin. The VLB molecule is formed by connecting a vindoline moiety (VM) molecule with a catharanthine moiety (CM) molecule through a carbon-carbon bond, which is a larger molecule. When the CM molecule exists in the middle of α, β-tubulin interface, the dissociation Δ G of α, β-tubulins is 46.2 kJ·mol −1, during which the CM moves with β-tubulin. When the VM molecule exists between the middle of α, β-tubulin interface, the dissociation Δ G of α, β-tubulins is 86.7 kJ·mol −1, during which it moves with α-tubulin. Therefore, the VLB molecule is like a double-sides tape to stick α-tubulin and β-tubulin together. The VLB molecule intervenes the dynamic equilibrium between dissociation and aggregation of α-tubulin and β-tubulin by a double-sides sticking mechanism to exert high activity with toxicity against cancer cell. Besides, our results demonstrate that VLB has its structural basis for anticancer cytotoxicity due to its two compositions composed of a CM molecule and a VM molecule although they have little toxicity against cancer cell alone.